Multiple sclerosis (MS) is an immune-mediated, inflammatory disorder of the central nervous system. Despite being classically considered a demyelinating disorder, it has been demonstrated that neuro-axonal injury occurs early in the disease course and represents the pathologic substrate for permanent neurological disability in people with MS (PwMS). In clinical practice, disease monitoring in PwMS is performed by clinical evaluation and use of conventional magnetic resonance imaging (MRI) measures, including new T2 lesions and/or presence of T1 post-gadolinium (Gd) enhancing lesions. Notably, these conventional MRI measures assess for the presence of inflammatory disease activity rather than neuro-axonal loss and are only modestly associated with clinical measures of disability in MS, a phenomenon known as the ?clinico-radiological paradox?. There is an unmet need in MS for a biomarker that may identify PwMS with ongoing neuro-axonal damage prior to the accrual of permanent clinical disability, in order to allow for timely intervention. Neurofilaments are neuron-specific cytoskeletal proteins that are released following neuro-axonal damage. Increased neurofilament light chain (NfL) levels have been found in the blood and cerebrospinal fluid (CSF) in several neurological disorders, including MS. In MS, there is evidence that serum NfL (sNfL) levels correlate closely with CSF NfL levels, are associated with clinico-radiological measures of disease activity, are modulated by disease modifying therapies (DMTs), and predict disability worsening and brain atrophy. However these data are derived mainly from small, single-center studies, and the influence of factors including demographics, disease subtype, and co-morbid conditions on sNfL levels in MS remains poorly characterized. It is also remains unclear if sNfL levels may be used to monitor response to therapy, guide decision-making regarding potency of immunotherapy, and predict long-term outcomes. While, given this emerging evidence, there is great interest in sNfL for use as a prognostic and monitoring biomarker of neuro-axonal injury in MS, further clinical validation is necessary in larger, demographically diverse, clinically heterogeneous, multi-center cohorts. Furthermore, it is of utmost importance that validation is performed utilizing a robust, scalable assay that may be rapidly implemented in the clinical realm. We plan to measure sNfL utilizing a novel automated immunoassay (Siemens Healthineers; performed on an existing clinically available platform) in serum samples from two large multi-center studies: 1) MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a network of 10 healthcare institutions in the United States and Europe, merging research with ongoing patient care by collecting standardized clinical/imaging data and biospecimens during routine medical visits. As of February 1st, 2019, >15,000 patients have opted to participate in MS PATHS with biospecimens already available for >5,000 patients. 2) TREAT-MS (Traditional versus Early Aggressive Therapy for Multiple Sclerosis) is an ongoing, pragmatic, randomized controlled trial, designed to evaluate in treatment nave MS patients whether an ?early aggressive? therapy approach, versus starting with a traditional, first-line therapy approach, influences the longer-term risk of disability (at 48 months). TREAT-MS is prospectively recruiting 900 subjects across ~45 sites in the US (83 enrolled as of February 1st, 2019) with anticipated enrollment of 700 subjects in the bio-banking sub-study. We anticipate that large-scale clinical validation of sNfL in MS as a prognostic and monitoring tool in this study will lead to submission to the FDA of a full qualification package and will lead to availability of the first blood-based biomarker of MS.